CTGF (connective tissue growth factor) is a secreted protein rich in cysteine residues with a molecular weight of about 36 to 38 kDa, belonging to a CCN family (Non-Patent Document 1), and has been conventionally known to be induced by TGF-β that can be considered to be the most important growth factor in fibrosis (Non-Patent Document 2). Therefore, it is suggested that TGF-β induces CTGF and the induced CTGF promotes the fibrosis of organs or tissues, and it is believed that CTGF plays an important role in fibrosis, cell proliferation, metabolism of the extracellular matrix, angiogenesis, arteriosclerosis, and the like (Non-Patent Document 3).
It has become known that there are many domains present in CTGF, which interact with other factors. Among them, it is known that CTGF is coupled directly with TGF-β or BMP4 via von Willebrand C domain, and causes the promotion of TGF-β signaling or the inhibition of BMP signaling (Non-Patent Document 4).
It has become known that expression of CTGF is increased in various renal diseases (for example, chronic kidney disease, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, focal segmental glomerulosclerosis, ANCA-related nephritis, acute progressive glomerulonephritis, chronic transplant nephropathy, nephrotic syndrome, lupus nephritis and membranoproliferative glomerulonephritis) (Non-Patent Document 5), and it has been reported that CTGF is deeply involved in fibrosis (Non-Patent Document 6).
In addition, it has been reported that CTGF is involved in various types of fibrosis (scleroderma, interstitial lung disease, pulmonary fibrosis diseases such as idiopathic pulmonary fibrosis, fibrosis caused by chronic hepatitis B or C, radiation-induced fibrosis, fibrosis caused by wound healing, and cardiac hypertrophy and fibrosis), vascular proliferative diseases, diabetic retinopathy, cancer, and the like, and thus, it can be thought that CTGF could be a new therapeutic target (Non-Patent Documents 7 and 8).
Therefore, if a monoclonal antibody which specifically binds to CTGF and has an activity inhibiting various actions of CTGF can be developed, the monoclonal antibody is expected to be useful for diagnosis, prevention or treatment of various diseases in which CTGF is involved in pathogenesis.
As an antibody showing an inhibitory function against human CTGF, which have been hitherto studied, human monoclonal antibodies M84 and M320 (Patent Document 1), CLN1 (Patent Document 2), a mouse monoclonal antibody CTGF-m2-1 (Patent Document 3), and the like have been reported. Among them, CLN1 has been investigated in most detail, and its effect has been identified in an interstitial pulmonary fibrosis model or a renal interstitial fibrosis model by unilateral ureteral ligation. CLN1 is studied in clinical trial (Phase II) as FG-3019.
However, it cannot be said that conventional antibodies have sufficient binding activity for CTGF, and have sufficiently strong neutralizing activity for CTGF from a viewpoint of therapeutic effectiveness.
In general, examples of the major factors defining the effective doses of the antibody pharmaceuticals include the binding activity or neutralizing activity which the antibody has for an antigen, and the amount of an antigen present in the body. However, it can be said that improvement of the binding activity or the neutralizing activity directly leads to reduction in the dose, and as a result, it is a very useful improvement, leading to reduction in the economic burden of a patient or medical cost.
For these reasons, it is essential to acquire an anti-human CTGF antibody having stronger binding activity or neutralizing activity than conventional antibodies for the purpose of using in prevention or treatment of various diseases, in which CTGF is involved in the pathogenesis.